Evaluation of the Anti-<i>Histoplasma capsulatum</i> Activity of Indole and Nitrofuran Derivatives and Their Pharmacological Safety in Three-Dimensional Cell Cultures

• Main Authors: Carolina Orlando Vaso (Author), Níura Madalena Bila (Author), Fabiana Pandolfi (Author), Daniela De Vita (Author), Martina Bortolami (Author), Jean Lucas Carvalho Bonatti (Author), Rosângela Aparecida De Moraes Silva (Author), Larissa Naiara Carvalho Gonçalves (Author), Valeria Tudino (Author), Roberta Costi (Author), Roberto Di Santo (Author), Maria José Soares Mendes-Giannini (Author), Caroline Barcelos Costa-Orlandi (Author), Luigi Scipione (Author), Ana Marisa Fusco-Almeida (Author)
• Format: Book
• Published: MDPI AG, 2022-05-01T00:00:00Z.
• Subjects: article
• Online Access: Connect to this object online.

Summary

<i>Histoplasma capsulatum</i> is a fungus that causes histoplasmosis. The increased evolution of microbial resistance and the adverse effects of current antifungals help new drugs to emerge. In this work, fifty-four nitrofurans and indoles were tested against the <i>H. capsulatum</i> EH-315 strain. Compounds with a minimum inhibitory concentration (MIC₉₀) equal to or lower than 7.81 µg/mL were selected to evaluate their MIC₉₀ on ATCC G217-B strain and their minimum fungicide concentration (MFC) on both strains. The quantification of membrane ergosterol, cell wall integrity, the production of reactive oxygen species, and the induction of death by necrosis-apoptosis was performed to investigate the mechanism of action of compounds <b>7</b>, <b>11</b>, and <b>32</b>. These compounds could reduce the extracted sterol and induce necrotic cell death, similarly to itraconazole. Moreover, <b>7</b> and <b>11</b> damaged the cell wall, causing flaws in the contour (<b>11</b>), or changing the size and shape of the fungal cell wall (<b>7</b>). Furthermore, <b>7</b> and <b>32</b> induced reactive oxygen species (ROS) formation higher than <b>11</b> and control. Finally, the cytotoxicity was measured in two models of cell culture, i.e., monolayers (cells are flat) and a three-dimensional (3D) model, where they present a spheroidal conformation. Cytotoxicity assays in the 3D model showed a lower toxicity in the compounds than those performed on cell monolayers. Overall, these results suggest that derivatives of nitrofurans and indoles are promising compounds for the treatment of histoplasmosis.

Item Description

10.3390/pharmaceutics14051043
1999-4923